Abstract
目的
探讨合并急性肾损伤(acute kidney injury,AKI)的感染性心内膜炎(infective endocarditis,IE)患者的临床特点,分析此类患者的围术期及预后情况。
方法
回顾性分析2002年1月至2018年6月在北京大学第一医院心脏外科就诊的IE患者100例。根据患者术前情况及AKIN标准,分为AKI组和非AKI组,比较两组临床资料和术后并发症的差异,随访对比两组预后情况。
结果
AKI组21例和非AKI组79例,总体平均年龄(43.7±15.7)岁,男女比例3 :1,IE患者中AKI的发生率为21%。两组间年龄、性别构成差异无统计学意义。与非AKI组相比,AKI组患者皮疹及下肢水肿的比例更高(P=0.017和P=0.001),尿潜血及尿蛋白阳性率更高(P<0.001),血红蛋白及血清白蛋白水平更低(P<0.001),临床心功能更差(P=0.033)。两组病原菌检出率及病原菌种类差异无统计学意义。除9例患者拒绝手术外,其余91例患者均接受了体外循环下心内直视手术,包括AKI组19例和非AKI组72例。AKI组患者围术期红细胞用量更多(P=0.010),术后呼吸机使用时间及监护室停留时间更长(P=0.028和P=0.003)。以两组患者术前末次肌酐为基准,AKI组新发术后肾功能不全比例更高(P=0.004)。两组患者院内死亡率差异无统计学意义(P=0.463),随访期间两组生存率差异未见统计学意义(P=0.581)。
结论
与非AKI组相比,合并AKI的IE患者围术期并发症发生率更高,但两组患者院内死亡率及预后无明显差异。
Keywords: 急性肾损伤, 心内膜炎, 细菌性, 心脏外科手术
Abstract
Objective
To investigate the clinical features and treatment of infective endocarditis (IE) patients with acute kidney injury (AKI), and to compare the adverse complications and outcome with IE patients without AKI.
Methods
Clinical data of 100 IE cases in Peking University First Hospital from January 2002 to June 2018 were retrospectively reviewed. The patients were divided into AKI group (n=21) and non-AKI group (n=79) based on the AKI network (AKIN) definition. The clinical data and prognosis were compared between the two groups.
Results
The incidence of AKI was 21%. The average age was (43.7±15.7) years, and the ratio of male to female was 3 :1. There was no significant diffe-rence in age and gender between the two groups. Compared with non-AKI group, the AKI group had more rash and lower limbs edema (P=0.017 and P=0.001), higher urine blood and protein positive rate (both P<0.001). Lower hemoglobin and serum albumin level (both P<0.001), worse clinical cardiac function (NYHA Ⅲ-Ⅳ, P=0.033) were found in AKI group compared with non-AKI group. There was no significant difference in microbiologic positive rate and pathogenic bacteria sorts between the two groups. Nine patients refused surgery, and the other 91 cases underwent cardiac surgery with cardiopulmonary bypass under general anesthesia, including 19 cases of AKI group and 72 cases of non-AKI group. The ventilation time and intensive care unit (ICU) stay time were longer in AKI group than in non-AKI group (P=0.028 and P=0.003). AKI group needed more red blood cell transfusion (P=0.010). Using the last serum creatinine before surgery as basic level, there was more new-onset AKI cases in AKI group than in non-AKI group. During the median follow-up time 42 months, there was no significant difference in perioperative and follow-up mortality between the two groups (P=0.463 and P=0.581).
Conclusion
More perioperation complications occurred in IE patients with AKI, but no significant difference in in-hospital and follow-up mortality between the AKI and non-AKI groups was observed.
Keywords: Acute kidney injury, Endocarditis, bacterial, Cardiac surgical procedures
感染性心内膜炎(infective endocarditis,IE)是具有较高死亡率的感染性疾病,越来越多的患者需要外科手术干预[1]。目前已有大量文献证实,术前肾功能不全是心脏术后不良预后的独立危险因素[2]。与其他心脏手术患者不同,IE患者的术前肾功能不全常表现为由于感染、栓塞等多种因素造成的急性肾损伤(acute kidney injury,AKI)[3,4]。对于IE患者,手术治疗可以清除感染灶、减少栓塞,可能有利于肾功能恢复。本研究旨在初步探讨合并AKI的IE所具有的临床特点以及治疗和预后情况。
1. 资料及方法
1.1. 研究对象
连续纳入2002年1月至2018年6月在北京大学第一医院住院的IE患者,排除透析依赖患者,共100例入选,其中男性75例、女性25例,发病年龄11~81岁。IE的诊断符合修正的DUKE标准[5],AKI的诊断符合2005年急性肾损伤网络工作组(acute kidney injury network, AKIN)标准[6],根据术前是否合并AKI将IE患者分为AKI组(n=21)和非AKI组(n=79)。
1.2. 研究方法
收集各组患者的基本资料、临床特点以及术后不良事件发生情况,包括住院期间死亡、并发症、机械通气时间延长(术后至拔出气管插管停止使用呼吸机之间的时间超过24 h)、术后重症监护治疗病房(intensive care unit,ICU)停留时间延长(手术结束至ICU转出时间超过72 h)。
1.3. 统计学分析
采用SPSS 19.0软件进行统计学分析。计数资料以例数和百分率表示,组间比较采用卡方检验,计量资料以均数±标准差表示,正态分布数据组间比较采用t检验,非正态分布数据采用非参数检验。以P<0.05为差异有统计学意义。
2. 结果
2.1. 临床资料比较
总体平均年龄(43.7±15.7)岁,男女比例3 ∶1。AKI组和非AKI组在年龄、性别构成上差异无统计学意义(表1)。与非AKI组相比,AKI组患者出现皮疹及下肢水肿的比例更高(P=0.017,P=0.001)。与非AKI组相比,AKI组肌酐水平、尿潜血及尿蛋白阳性率更高(P<0.001),血红蛋白及血清白蛋白水平更低(P<0.001)。虽然超声检查提示两组患者左心室射血分数差异无统计学意义(P=0.249),但AKI组的临床心功能分级更差(P=0.033)。
1.
AKI组与非AKI组临床资料比较
Comparison of clinical features of two groups
| Items | AKI group (n=21) |
Non-AKI group (n=79) |
P |
| AKI, acute kidney injury; SCr, serum creatinine; Alb, serum albumin; CRP, C-reactive protein; LVEF, left ventricular ejection fraction; NYHA, New York Heart Association. Data are shown as x±s or n(%). | |||
| Age/years | 45.9±14.5 | 43.3±16.3 | 0.511 |
| Male | 13 (61.9) | 62 (78.5) | 0.119 |
| Hypertension | 7 (33.3) | 25 (31.6) | 0.883 |
| Diabetes | 4 (19.0) | 7 (8.9) | 0.185 |
| Fever | 19 (90.5) | 71 (89.9) | 0.935 |
| Lower limbs edema | 11 (52.4) | 13 (16.5) | 0.001 |
| Rash | 6 (28.6) | 7 (8.9) | 0.017 |
| Arthralgia | 2 (9.5) | 8 (10.1) | 0.935 |
| Short of breath | 11 (52.4) | 32 (40.5) | 0.329 |
| Stroke | 1 (4.8) | 16 (20.3) | 0.093 |
| Hemoglobin/(g/L) | 96.1±15.0 | 116.0±20.7 | <0.001 |
| Peak SCr preoperation/ (μmol/L) |
313.0±187.5 | 87.8±19.2 | <0.001 |
| Alb/(g/L) | 32.4±6.2 | 37.6±5.7 | <0.001 |
| CRP/(mg/L) | 54.5±42.1 | 64.7±56.5 | 0.442 |
| Urine blood positive | 14 (66.7) | 20 (25.3) | <0.001 |
| Urine protein positive | 20 (95.2) | 29 (36.7) | <0.001 |
| LVEF/% | 63.7±11.9 | 66.5±9.3 | 0.249 |
| NYHAⅢ-Ⅳ | 9 (42.9) | 16 (20.3) | 0.033 |
2.2. 感染病原菌及肾活检病理情况
共有54例患者血培养阳性,病原菌检出率为54.0%,两组间病原菌检出率差异无统计学意义(P=0.249)。两组检出率最高的病原菌均为链球菌及葡萄球菌,非AKI组的链球菌检出比例稍高,AKI组的葡萄球菌检出比例稍高,但各病原菌检出率在两组间差异均无统计学意义(表2)。
2.
两组间感染病原菌比较
Pathogenic bacteria comparison between AKI and non-AKI group
| Items | AKI group (n=21) |
Non-AKI group (n=79) |
P |
| G-, Gram staining negative. | |||
| Blood culture positive,n (%) | 9 (42.9) | 45 (57.0) | 0.249 |
| Pathogenic bacteria, n (%) | |||
| Streptococci | 3 (14.3) | 28 (35.4) | 0.062 |
| Staphylococcus | 3 (14.3) | 8 (10.1) | 0.588 |
| Enterococcus | 1 (4.8) | 4 (5.1) | 0.955 |
| G- bacillus | 2 (9.5) | 5 (6.3) | 0.610 |
患者均出现了心内赘生物或瓣膜损害,最常见部位为二尖瓣(53.0%)和主动脉瓣(52.0%),两组间赘生物位置差异无统计学意义(表3)。
3.
AKI组及非AKI组间赘生物位置比较
Comparison of vegetation location between AKI and non-AKI groupn (%)
| Vegetation location | AKI group (n=21) |
Non-AKI group (n=79) |
P |
| Other: tricuspid valve 4 cases, pulmonary valve 3 cases, ventricular septum 1 case and doctus arteriosus 1 case. | |||
| Aorta valve | 14 (66.7) | 38 (48.1)) | 0.130 |
| Mitral valve | 8 (38.1) | 45 (57.0) | 0.124 |
| Other | 3 (14.3) | 6 (7.6) | 0.341 |
5例患者进行了肾活检,均为AKI组。其病理类型分别为:2例局灶增生性肾炎、1例新月体肾炎、1例局灶坏死性肾炎、1例抗中性粒细胞胞浆抗体(anti-neutrophil cytoplasmic antibodies,ANCA)相关性多血管炎肾损害合并免疫复合物介导的肾小球肾炎。
2.3. 治疗及预后
9例患者拒绝手术,其余91例患者均接受了体外循环下心内直视手术,其中AKI组19例、非AKI组72例(表4)。与非AKI组相比,AKI组的患者围术期红细胞用量更多(P=0.010),术后呼吸机使用时间及ICU停留时间更长(P=0.028和P=0.003)。以两组术前最后一次肌酐水平作为基线,根据AKIN诊断标准,即术后48 h内肌酐水平较术前升高3 mg/L或1.5倍及以上,AKI组术后出现AKI概率更高(P=0.004)。两组患者院内死亡率差异无统计学意义(P=0.463)。
4.
AKI组和非AKI组术后临床资料比较
Comparison of perioperative complications between two groups
| Items | AKI group (n=19) | Non-AKI group (n=72) | P |
| CHD, congenital heart disease; CABG, coronary artery bypass grafting; CPB, cardiopulmonary bypass; RBC, red blood cell; ICU, intensive care unit; AF, atrial fibrillation. | |||
| Surgery, n (%) | |||
| Valve replacement | 17 (89.5) | 65 (90.3) | 0.917 |
| CHD repair | 4 (21.1) | 7 (9.7) | 0.178 |
| CABG | 1 (5.3) | 4 (5.6) | 0.960 |
| Operative condition, x±s | |||
| CPB duration/min | 128.3±58.9 | 115.9±48.2 | 0.344 |
| Aortic clamping duration/min | 92.6±54.6 | 81.7±36.5 | 0.419 |
| RBC transfusion/IU | 7.7±3.7 | 5.0±3.9 | 0.010 |
| Drainage after surgery/mL | 1 048.9±655.8 | 758.9±565.3 | 0.058 |
| Complications, n (%) | |||
| Prolonged ventilation time | 6 (31.6) | 8 (11.1) | 0.028 |
| Prolonged ICU stay time | 12 (63.2) | 19 (26.4) | 0.003 |
| Low cardiac output | 2 (10.5) | 2 (2.8) | 0.143 |
| New onset of AF | 4 (21.1) | 6 (8.3) | 0.115 |
| New onset of stroke | 1 (5.3) | 4 (5.6) | 0.960 |
| Acute kidney injury | 13 (68.4) | 23 (31.9) | 0.004 |
| In-hospital death | 0 | 2 (2.8) | 0.463 |
至出院时19例AKI组患者中15例肌酐水平已恢复正常。91例手术患者中有73例获得远期随访资料,包括AKI组17例和非AKI组56例,中位随访时间42个月,随访期间两组均无IE复发,生存率差异无统计学意义(Log-Rank检验,P=0.581,图1)。
1.
AKI组和非AKI组生存曲线
Survival curves of AKI and non-AKI group
3. 讨论
IE的年发病率约为3/10万~10/10万[7,8],近十年来其发病率逐渐上升,且呈现老龄化趋势。尽管IE可以通过抗生素及外科手术治愈,但IE患者的全因死亡率仍是正常人群的2.27倍[9]。
AKI是IE的常见合并症,发生率为9%~21%[3],本组患者AKI的发生率为21%。导致IE患者术前发生AKI的因素包括以下几个方面:(1)血管炎及免疫复合物形成、沉积所导致的肾小球肾炎[10];(2)菌血症引发的肾动脉细菌栓塞;(3)肾毒性抗生素(如万古霉素)的应用;(4)瓣膜损毁导致的心力衰竭、血流动力学紊乱引起的肾血流灌注减低等。
IE的致病菌在不同国家和地区间存在差异,链球菌是发展中国家IE的最常见致病菌[11]。近50年来,在发达国家和高收入地区,葡萄球菌已超过链球菌成为IE的首位致病菌[1,7,12]。本研究检出致病菌的患者中,链球菌占57.4%(31/54),葡萄球菌占20.4%(11/54),AKI组葡萄球菌检出率高于非AKI组(14.3% vs. 10.1%), 链球菌检出率低于非AKI组(14.3% vs. 35.4%)。有研究发现,近50%感染葡萄球菌的IE患者存在心脏赘生物栓塞事件,远超其他致病菌[13]。动物实验表明,葡萄球菌分泌的超抗原,如葡萄球菌内毒素C(staphylococcal enterotoxin C,SEC),是参与心脏赘生物形成的重要因素,其引发的免疫反应是肾损伤的诱因[14]。我们推测,葡萄球菌感染可能是IE患者发生肾损伤的高危因素。
本研究发现AKI组患者出现皮疹的比例更高。IE常见的皮疹为免疫因素引起的Osler结节和化脓性栓塞引起的Janeway损害,由于免疫激活和肾栓塞亦为AKI的病因,AKI组皮疹高发可能与之相关。与非AKI组相比,AKI组患者下肢水肿发生比例更高,就诊时临床心功能更差,可能原因为肾损害导致的水钠潴留;同时IE导致的心力衰竭和血流动力学紊乱也会加重肾损害,导致心肾综合征。
由于肾受累,AKI组患者出现血尿、蛋白尿比例明显较高,血清白蛋白水平低于非AKI组,原因可能是蛋白尿导致蛋白丢失、水钠潴留的稀释作用以及感染引起的肝合成功能下降。既往研究显示,低蛋白血症也是IE术后死亡的独立危险因素[11,15]。AKI组术前贫血程度较非AKI组严重,围术期红细胞用量也多于非AKI组。肾功能不全会引起促红细胞生成素(erythropoietin,EPO)的合成减少,导致肾性贫血发生,提示对于合并AKI的IE患者,应关注白蛋白及血红蛋白水平,术前应充足备血。
手术治疗IE逐渐被重视,适时的手术能降低IE死亡和栓塞的风险,改善患者的预后[16,17]。大量研究显示,心脏外科手术前肾功能不全及术后AKI均与患者的不良预后相关,心脏外科手术后AKI的发生率为1%~30%[18],围术期低灌注、体外循环炎性反应是其主要原因。但对于IE患者,手术可以清除感染性赘生物,减少全身炎性反应,同时对心瓣膜功能的重建也起到改善血流动力学、改善肾灌注的作用。因此,手术对IE患者肾功能的影响是多方面的,尤其对于术前合并AKI的患者,但这种影响是不确定的。
本研究术前即合并AKI的IE患者术后AKI发生率为 68.1%,明显高于术前未合并AKI组(31.9%)和总体IE患者(39.6%)。尽管两组患者术后血肌酐水平在72 h内均有升高,但至术后2周AKI组大部分患者血肌酐水平恢复正常。有研究认为,术前合并肾功能不全可能导致IE患者院内死亡率增加[19]。Buchholtz等[20]跟踪了231例接受外科手术治疗的IE患者,平均年龄(61.3±15.0)岁,平均随访453 d,其中76例(32%)死亡,入院时肌酐清除率是死亡的独立危险因素。本研究发现,与非AKI组相比,AKI组的ICU停留时间及呼吸机使用时间更长。以术前最后一次血肌酐水平作为基线,AKI组术后新发AKI的概率更高,因此,对于术前合并AKI的IE患者,应重视围术期肾功能监测,尽可能地避免使用肾毒性药物,维持体外循环灌注压并避免术后低血压,以保证肾灌注,可能会有利于肾功能的恢复。本研究两组患者院内死亡及远期生存方面差异均无统计学意义,总体院内死亡率也低于国外报道,出现这种差异的原因可能为:(1)IE发病在发达国家呈现老龄化趋势,国外研究人群年龄更高,可能纳入了更多的高危患者;(2)国外研究仅以肾功能分组,慢性肾功能不全不能通过心脏外科手术改善,而本研究根据术前是否合并AKI进行分组,心脏外科手术可能会去除相关病因。也有学者认为,并非术前肾功能水平而是术后的肾功能衰竭增加了IE的死亡风险[4],本研究也从侧面支持了这个结论,但因为终点事件数较少,本研究并未采用多因素分析进行比较,将来尚需更大规模的多中心研究来验证。
总之,多种因素导致IE患者术前AKI的发生,心脏外科手术能够去除感染灶,减轻炎性反应,减少栓塞的发生。虽然合并AKI的IE患者围术期并发症发生率较高,但大部分患者术后肾功能可以恢复,与非AKI组相比,其院内死亡率及预后差异并无统计学意义,手术治疗对于合并AKI的IE患者是安全且有效的。
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